Project Summary How host-environment homeostasis is established and maintained at mucosal surfaces are fundamental concepts in immunology. Due to the abundance of IgA specifically at mucosal surfaces, it is thought to be a key regulator at these barriers. However, the relevance of IgA in shaping microbial communities in humans and the role IgA plays in human gut barrier integrity is not well defined. These gaps in knowledge are an important problem because until they are filled, a full understanding of host-environment homeostasis will remain incomplete. The long-term goal is to understand the role of B lineage cells in host-environment homeostasis and immune fitness. In pursuit of this goal, the objective of this particular application is to explore the role that IgA plays influencing gut barrier function and in managing microbial membership and diversity in humans. The central hypothesis is that IgA can regulate host-microbe interactions and gut barrier integrity at mucosal surfaces. This hypothesis was formulated based on mouse model findings of commensal microbe-focused IgA repertoires in small intestine and on findings that IgA in mice may regulate the microbial membership and diversity. The rationale for the proposed research is that, once accomplished, the role of IgA in regulating microbial membership and gut barrier function in humans will be clarified. The central hypothesis will be tested by way of three specific aims: 1) Explore the effect of IgA deficiency on the human microbiome; 2) Explore the extent of symbiont-coated IgM compensation in IgA deficiency; and 3) Explore the role of IgA-deficiency on barrier integrity. Aim 1 is expected to reveal the role of IgA in regulating microbial membership and diversity. Aim 2 is expected to reveal the role of IgM in potentially compensating for lack of IgA. It is also expected to uncover the degree to which lack of IgA in the serum corresponds to lack of IgA coating of bacteria in the intestinal lumen. Aim 3 is expected to uncover the degree to which lack of IgA may be associated with barrier dysfunction. Together, these anticipated results and new approaches are expected to have an important positive impact, as they break new ground into human IgA function. Results promise to deepen the understanding of host-microbe homeostasis and fundamentally advance the field of human immunology. The proposed work is innovative, because it is the first study to directly assess the role of human IgA in human microbial ecology and intestinal barrier integrity. The proposed work is significant because it is a key step in a continuum of research that is required to achieve a full understanding of IgA's role in the regulation of host-microbe homeostasis in humans.